Hypoxia-inducible factor-1α (HIF-1α), a well-identified hypoxia-related protein, is involved in regulating the biological functions of various cell types including neurons. The traditional biological function of HIF-1α is promoting the transcription of some pro-survival genes when exposing to low oxygen conditions. Meanwhile, some studies also point out that HIF-1α shows the detrimental role in several central nervous system (CNS) disorders. Up to now, the knowledge of HIF-1α function in CNS is still limited. To investigate whether HIF-1α is involved in CNS impairment and repair, we employed a traumatic brain injury model in adult rats. Upregulation of HIF-1α was observed in the injured brain cortex by western blot analysis and immunohistochemistry staining. Terminal deoxynucleotidyl transferase deoxy-UTP nick-end labeling (TUNEL) and 4',6-diamidino-2-phenylindole (DAPI) staining suggested that HIF-1α was relevant to neuronal apoptosis after brain injury. In addition, glutamate excitotoxic model of primary cortex neurons was introduced to further investigate the role of HIF-1α in neuronal apoptosis; the result implied HIF-1α was associated with the regulation of p53 and BNIP3 in the apoptotic neurons. Based on our data, we suggested that HIF-1α might play an important role in neuronal apoptosis after traumatic brain injury in rat, which might also provide a basis for the further study on its role in regulating the transcription of target genes in apoptotic neurons, and might gain a novel strategy for the clinical therapy for traumatic brain injury.